The use of radiolabelled steroids for in vivo receptor binding assays is well known; generally, the efficacy of particular radiolabelled steroids is evaluated in competitive binding assays employing non-radioactive analogue as competitor. The radiolabelled steroid, to be of use in nuclear medicine applications, should exhibit a high specific activity, good chemical stability, and a high in vivo receptor binding affinity.
Since stability is essential, halogenation of the aromatic ring of native steroids has been proposed, as it is known that steroids in which the aromatic ring of the steroid nucleus is halo-substituted are generally more stable than the same steroids wherein an aliphatic carbon is halo-substituted. In some instances, however, stabilization of steroids by halogenation or radiohalogenation has significantly reduced the biological activity of the steroid so that the derivative is useless as a practical matter in applications requiring a high in vivo binding affinity between the receptor and stabilized compound. For example, estradiol brominated in the 4-position with .sup.77 Br has a high specific activity, and good chemical stability; receptor binding studies, however, indicate that 4-.sup.77 Br-estradiol has a low in vivo binding affinity for estrogen receptors, probably owing to the close proximity of the halo and hydroxyl substituents on the 3-phenol aromatic ring.
It is thus accordingly proposed to halogenate estrogens in the 1-position to stabilize the compounds while lessening the halo/hydroxyl interaction on the aromatic ring, thereby preserving biological activity of the native estrogen. The present process avoids known synthesis difficulties which have previously precluded preparation of comparable 1-haloestrogens, particularly the fact that, while the 2- and 4-positions of the phenol are highly active, the 1-position is meta to the hydroxy group, and is consequently deactivated; preferential direct electrophilic substitution at the 1-position of the aromatic ring is thus highly improbable.